The broad long term objectives of this proposal are to investigate the role of cellular immunity in the pathogenesis of atherosclerosis using several recently developed models in mice in which reproducible atherosclerotic lesions can be induced. Our immediate goals are to focus on the specific role that T lymphocytes play. Our hypothesis is that if T cells are necessary In the' pathogenesis of atherosclerosis, the development and progression of atherosclerotic lesions will be prevented or retarded in mice with selective T cell deficiencies. To test this hypothesis we plan to evaluate the development of atherosclerotic lesions in the following models: 1) Mice with their T cell abated using anti-CD4 and anti-CD8 monoclonal antibodies and fed a high fat atherogenic: diet; 2) Mice that lack CD4+ or CD8+ lymphocytes due to T cell receptor mutations generated by gene disruption and fed a high fat atherogenic diet; and 3) Euthymic apo E deficient mice with their T cells ablated by monoclonal antibodies as described above (these mice develop hypercholesterolemia and atherosclerotic lesion on normal low fat mouse chow as well as high fat diets). We already have preliminary data suggesting that atherosclerosis is at least in part T cell mediated. Accordingly, our long term goals will include plans to further investigate the possible autoimmune nature of the disease including determining the nature of the autoantigens, determining if there is restricted clonality of T cells in this disease and determining if it will be possible to prevent or inhibit the disease by some of the exiting new therapeutic approaches to autoimmune disease such as MHC blockade or T cell receptor therapy. Other long term goals include plans to investigate the role of cytokines, eicosanoids and hormones in the mouse model using both immunologic and molecular methods. The mouse would appear to be a good model for such studies because of the wide variety of recombinant cytokines, cytokine; molecular probes and anti- cytokine monoclonal antibodies available. The information acquired in these studies may help provide a focus for our long term goals and may also suggest more rational and potent therapeutic approaches to prevent or interrupt the progression of the disease. Finally, the successful completion of these studies might also lead to the extension of these studies to humans and the possibility that some of the above mentioned new therapeutic approaches could be applied to the prevention and treatment of human atherosclerosis.